Proteases cleave peptide bonds between adjacent L-amino acids, rendering these peptides susceptible to degradation in the GIT. Artificial proteins or peptides composed of D-amino acids are largely resistant to proteolytic breakdown. However, when D-amino acids are substituted for all L-amino acids in a peptide/protein, the corresponding D-peptide/protein is a mirror image of the original peptide/protein and is likely to have modified or lost biological activity because of this change in conformation. Retro-inverted peptides are peptides having all D-amino acids but are synthesized in the reverse order or sequence compared to the original L-peptide/protein. The carboxy terminus of the original peptide/protein becomes the amino terminus (and vice versa) of the retro-inverted peptide/protein and the resulting side chain surface of the retro-inverted peptide/protein is similar to the original L-peptide/protein. The net result of combining D-enantiomers and reverse synthesis is that the positions of carbonyl and amine groups in each amide bond are exchanged while the position of side-chain groups is preserved (Brady, L. and Dodson, G., Nature, 368L:692-693 (1994); Jameson et al., Nature, 368; 744-746 (1994)). This alteration in the protein backbone is self compensating in that hydrogen-bond donors become hydrogen-bond acceptors (amide carbonyl groups) and vice-versa. When the position of the side-chains relative to the backbone are unchanged the modified surface of the retro-inverted peptide/protein is largely unaltered compared to the original L-peptide/protein.
Previously, as disclosed and claimed in WO 98/51325, which is hereby incorporated by reference in its entirety, we have identified random peptides and their fragments, motifs, derivatives, analogs or peptidomimetics thereof which are capable of specific binding to GIT transport receptors such as the D2H (human D2 clone), hSI (human sucrase isomaltose), HPT1 (human intestinal oligopeptide transporter) and hPEPT1 (human oligopeptide transporter) receptors (hereinafter “GIT targeting agents”). These GIT targeting agents are capable of facilitating transport of an active agent through a human or animal gastro-intestinal tissue and have use, for example, in facilitating transport of active agents from the lumenal side of the GIT into the systemic blood system and/or in targeting active agents to the GIT. Thus, for example, by binding (covalently or noncovalently) the GIT targeting agent to an orally administered active agent, the active agent can be targeted to specific receptor sites or transport pathways which are known to operate in the human gastrointestinal tract, thus facilitating its absorption into the systemic system. Preferably, the active agent is a drug or a drug-containing nano- or microparticle.